This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. To determine the role of the various nuclear receptors in the projects proposed in this COBRE, we are developing breeding colonies at KUMC of various nuclear receptor null (knockout) mice. Specific nuclear receptor knockout mice will be employed to determine the relationship between basal gene expression level and/or other measures of phenotype and the presence or absence of these nuclear receptors. At the present time we have the following null colonies: PXR, AhR, PXR[unreadable], CAR, PPAR[unreadable], Nrf2, HNF1[unreadable], and HNF4[unreadable]. For the projects of this proposal, we will also need to obtain and/or develop SHP, FXR, and RXR[unreadable]. So far, frozen livers of those knockout mice and strain matched wild-type mice have been generously provided by Drs. Frank Gonzalez (PPAR[unreadable], PPARgamma, HNF4[unreadable], FXR), Wen Xie (PXR, PXR/CAR double knockout out), David Mangelsdorf (LXR), David Moore (CAR), Marie Demay (VDR), Douglas Forrest (TRbeta), and Henry Sucov (RARbeta). We need to maintain our existing knockout mice colonies in numbers that permit experiments to be performed on demand, as well as engineer new knockouts or double knockouts as the needs arise.